Covalent modifications of protein by phosphorylation and oxidation are important mechanisms for the modulation of a plethora of cellular responses. Protein phosphorylation catalyzed by protein kinase C (PKC) has been linked to the regulation of cellular processes as diverse as ion channels, cellular metabolism, synaptic plasticity, and growth and differentiation. Neurogranin (Ng) is a specific in vivo PKC substrate highly concentrated in the neuronal cell bodies and dendrites within the cerebral cortex, hippocampus, and amygdala. Ng is a calcium- sensitive calmodulin (CaM)-binding protein that serves as a CaM buffer to regulate the calcium transient and formation of the calcium/CaM complex. The CaM-binding affinity of rodent Ng is modulated by PKC-mediated phosphorylation or oxidants (such as nitric oxide and hydrogen peroxide)-induced modification. To examine the role of Ng in neural function, mutant mice devoid of Ng were generated. Ng knockout (KO) mice develop normally but exhibit impairments of spatial learning and memory and the induction and expression of long term potentiation (LTP), an experimental model for investigating the synaptic basis of learning and memory in vertebrates. Ng KO mice also display a shift in the frequency response in favor of long-term depression at frequencies between 5 to 10 Hz, which occur naturally in the wild type mice during exploration. These deficits in the KO mice were accompanied by defective signal transduction mechanisms for the activation of calcium/CaM-dependent protein kinase II, PKC, and cAMP-dependent protein kinase (PKA). The phosphorylation of several downstream targets of kinases that are important for learning and memory, including mitogen-activated protein kinases and cAMP responsive element-binding protein, were severely attenuated. These findings may account for the poor performances of the Ng KO mice in behavioral tests for cognitive functions. The level of Ng in the hippocampus of both wild type and heterozygous mice was shown to correlate positively with the performance of mice in learning spatial tasks. We hypothesize that a higher level of Ng enables the neurons to maximize the activation of PKC at a given calcium influx by competitive binding to CaM. The activated PKC in turn stimulates adenylyl cyclase to increase cAMP and activation of PKA, and to upregulate the NMDA receptor channel to further potentiate calcium influx. We propose that Ng is an endogenous enhancer of learning and memory.